Xenotransplantation aims to provide a therapeutic solution to many patients that suffer tissue or organ dysfunction. However, porcine xenografts transplanted into primates are rejected by humoral and cellular responses resistant to immunosuppression. Ident ifying the molecular bases of xenograft rejection and developing strategies to overcome them is crucial to achieve long-term graft survival. Accordingly, this proposal aims to study the role of innate immunity in this rejection process and particularly, th e interaction of porcine CD200 (pCD200) and the human CD200 receptor (hCD200R). It also seeks to develop strategies that promote CD200R signalling to prolong xenograft engraftment. It is known that engagement of hCD200R triggers inhibitory effects in cells of myeloid lineage. In this work, the main objective is to clone and sequence the pCD200 cDNA, characterize the protein and assess its binding to hCD200R. It also aims to study the expression pattern of pCD200 to compare it to the mouse and human counterp arts. The porcine and human CD200 will be expressed on porcine cells by genetic engineering to assess its effects on human immune responses in vitro using mixed cultures. The function of CD200 can be further evaluated in combination with other approaches s uch as CD86 blockade. Animal models will follow to explore its potential protective effect in vivo. To this end, I will develop pig-to-mouse cellular transplant models to evaluate the efficacy of systemic CD200Ig treatments and/or CD200 overexpression on t he porcine donor cell. The in vivo studies will focus on studying the cellular immune rejection by histologic examination and the humoral response by determining the elicited antibody titers. If these strategies prolong xenograft survival, this study will represent a step forward toward the clinical use of xenogeneic cells and tissues.
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